Diphenylbutyl-1-acylpiperazines

ABSTRACT

Novel compounds of the formula ##STR1## wherein R&#39; is selected from the group consisting of alkyl straight or branch chained having from 2 to 10 carbon atoms, cycloalkyl having from 3 to 8 carbon atoms, aralkyl having from 7 to 9 carbon atoms, phenyl and substituted phenyl wherein the substituents of the substituted phenyl are selected from the group consisting of one to three F, Cl, Br, lower alkyl having from 1 to 5 carbon atoms, lower alkoxy having from 1 to 5 carbon atoms, alkylenedioxy having from 1 to 3 carbon atoms, --CF 3  and --CN and pharmaceutically acceptable salts thereof which have been found to have utility for therapeutic treatment of mental disorders by reducing anti-aggressive behavior and a process for making the compounds.

FIELD OF INVENTION

The present invention relates to novel diphenylbutyl-1-acylpiperazinesand their acid addition salts having pharmacologically valuableproperties, processes for the preparation thereof and therapeuticcompositions containing said compounds.

PRIOR ART

French Pat. No. 2,367,067 (CA 89: 24362 h) describes as having analgeticproperties piperazine derivatives of formula: ##STR2## wherein Rrepresents a lower unsaturated alkyl or furyl group or a lower alkylgroup optional substituted by a lower alkoxy group, R₁ and R₂ representa methyl or ethyl group, R₃ represents a hydrogen atom or a methyl or amethoxy or a hydroxy group, X is O, CO, CO₂, CR₄ R₅ or NCOR₆, R₄represents a hydrogen atom or a lower alkoxy or a lower acyloxy or ahydroxy group, R₅ represents a hydrogen atom or a phenyl group, R₆represents a lower alkyl group and n is 1, 2 or 3.

In the article "In vitro Metabolism of Lidoflazine by Rat and Dog LiverFractions" by W. Meuldermans et al in Arzneim.-Forsch./Drug Res. 27 (I)832 (1977) the compound1-acetyl-4-[4,4-(di-fluorophenyl)butyl]piperazine is incidentally shownas a Lidoflazine metabolite among a number of other metabolites in ascheme illustrating metabolic pathways of lidoflazine. However, saidcompound is only shown by means a formula and there are no statements atall concerning any properties of the compound.

DESCRIPTION OF THE INVENTION

It has now been found that compounds of formula I: ##STR3## wherein R'is alkyl straight or branch chained having from 2 to 10 carbon atoms,preferably 2-3 carbon atoms, cycloalkyl having from 3 to 8 carbon atoms,preferably 3 carbon atoms, aralkyl having from 7 to 9 carbon atoms orphenyl unsubstituted or substituted by one to three F, Cl, Br, loweralkyl having from 1 to 5 carbon atoms, lower alkoxy having from 1 to 5carbon atoms, alkylenedioxy having from 1 to 3 carbon atoms, --CF₃ or--CN substituents and their pharmaceutically acceptable saltsunexpectedly exhibit valuable anti-aggressive, antipsychotic andantidepressive properties. Furthermore, the compounds of formula Iexhibit very potent analgetic properties.

Among the compounds A described in the above mentioned French patentspecification No. 2,367,067, which have been found to possess analgeticproperties, the compound which is most closely related to the compoundsaccording to the present invention is the compound wherein R=ethyl, R₁=R₂ =methyl, X=CH-Ph, R₃ =H, n=2, which hereinafter is referred to ascompound A₁. However, said compound A₁ differs chemically in severalrespects from the compounds according to the present invention. Thus,the known compound A₁ have no fluorine substituents in the two benzenerings and furthermore, the known compound has methyl substituents inpositions 2 and 5 of the piperazine ring which is not the case for thecompounds according to the present invention. Fluorine substitution inthe para position of the benzene rings and hydrogen substitution inpositions 2 and 5 of the piperazine ring of the known compound A₁carried out separately or in combination in all cases substantiallyreduce the potency relative to compound A₁. However, it has according tothe present invention surprisingly been found that lengthening of theside-chain together with fluorine substitution in the para position ofthe benzene rings and the absence of any C-substitution in thepiperazine ring, i.e. the compound of Formula I according to the presentinvention wherein R'=ethyl, leads to a tenfold increase in potency andprolonged activity relative to compound A₁. This demonstrates theimportant and unexpected improvements obtained by means of the compoundsI according to the present invention as compared to the most closelyrelated prior art.

As already is pointed out above the cited article of Meuldermans et alonly by means of a formula shows the compound1-acetyl-4-[4,4-(di-fluorophenyl)butyl]piperazine, hereinafter referredto as compound B, as a metabolite among other metabolites in a scheme.The article contains no statements as to any properties of saidcompound. However, as will be shown in the tests of pharmacologicalproperties described in the present application said compound B isinferior to the compounds I of the present invention.

There is much evidence that psychopharmacology has been moving incircles in the search for new antipsychotic, antidepressant andantianxiety drugs ever since systemic methods of pharmacologicalscreening of such drugs in animals were introduced. Drugs that werepredicted to possess specific psychotrophic properties on basis of theirpharmacological resemblance to a traditional type of drug have in theclinical failed to be more effective than existing drugs. With regardsto neuroleptics, the search for cataleptic properties as well as forantagonism of amphetamine and apomorphine induced stereotypies havepreserved extrapyramidal side-effects in all drugs of this type hithertodeveloped.

Until recently the therapeutic efficacy of the neuroleptics wasconsidered to be closely associated with the extra pyramidal motoraction and was evaluated in terms of their ability to produce acharacteristic catalepsy in animals. It is however now believed that theextrapyramidal dysfunction is caused by blockage of the dopaminereceptors in the striatum (Hornykiewicz, O. in Handbook ofNeurochemistry, Lajtha, A. ed. Plenum Press New York 1973 p. 465)whereas the antipsycotic activity is due to a similar interaction in themesolimbic area of the brain (Anden, N. E. et al J. Pharm.Pharmacol.,25, 346 (1973); Bertholini, G. ibid. 28 429 (1976)).

Neither cataleptogenic properties nor antagonism of amphetamine orapomorphine induced stereotypies in animals are of any value aspredictors for antipsychotic potency by the drug in patients in theclinic. There is also a need for better antidepressants with fewer andless severe side effects, especially the cardiotoxic ones. Thetherapeutic effectiveness is still far from ideal. Still, in most caseselectroconvulsive treatment is more effective than any antidepressantdrug known today. Instead of present antidepressants having atherapeutic effectiveness in 65-75% of the patients one ought to pursuethe goal that future antidepressants be effective in more than 90% ofthe patients. Furthermore, recent antianxiety drugs are not trulyspecific. Beside relief of excessive anxiety and tension these drugsproduce side effects such as drowsiness, decrease of alertness anddisturbed psychomotor performance. A very pronounced drawback of the newdrugs is the tendency to create tolerance or physical dependence. Manytimes they have synergistic action when combined with a alcohol or otherdepressant drugs.

The compound presented in this invention constituting a new prototypewill be useful in the treatment of mental disorders or diseases in theperipheral nerve system based on the same mechanism of action as themental disorders. The term "treatment of mental disorders" is meant toinclude administration of the compounds of formula I to a patient whohas already been identified to suffer from psychotic disorders andpersonality disorders. (van Praag, H. M., in The Neurobiology ofDopamine, Horn, A. S. et al., Ed., Academic Press, 1979, p. 655).Contrary to classical neuroleptics and antianxiety drugs, the compoundsof formula I have a balanced activating potency and they shouldtherefore be useful as antidepressants. The compounds are also capableof relieving both physical and emotional pain.

The compound of formula I have a new pharmacological profile not seen inany compound described earlier. The compounds produce longlastinginhibition of aggressive behaviour without causing any sedation,catalepsy or ataxia. In contrast to typical neuroleptics the compoundsdo not antagonize the stereotypy induced in rats by amphetamine orapomorphine. These pharmacological properties mean that the compoundsshould not induce any acute extrapyramidal side effects or tardivedyskinesia on chronic administration. Furthermore, the compounds shouldnot interfere with alertness, mental performance or coordination ofmovements, which are of importance in out-patients (patients not stayingin hospitals). The compounds block condition avoidance response (CAR)and exploratory behaviour only at high doses. The potent activity inaggression tests, the effects on cognitive and integrative processes aswell as inhibition of [³ H]-spiroperidol binding in defined parts of thebrain are suggestive of future usefulness in psychotic conditions. Thecompounds show very potent analgetic properties, which are not reversedby naloxone.

The analgetic properties of the compounds, the lack of effect onconsciousness and the lack of being hypnotic or addictive imply that thecompounds should be very useful in the treatment of chronic pain indifferent diseases and also of acute pain in connection with operationsas well as in painful examinations. The analgetic and anti-inflammatoryeffects of the compounds, the effect on the immunologic system as wellas the psychotropic effect are suggestive of their future usefulness ingeriatric and rheumatoid patients.

The antianxiety effect and the protecting effect on induced stress inanimals exhibited by the compounds will be of value in the treatment ofdepressive illnesses and also of psychosomatic disorders such as ulcusin man.

The new compounds are very useful in the treatment of aggressivebehaviour in animals, especially in pigs, and also in promoting thedevelopment of a natural hierarchy in groups of animals without burstsof aggression and in calming of anxious and stressed animals.

The compounds have no or very few autonomical side effects and a lowdegree of toxicity.

According to further features of the present invention there areprovided the following processes for the preparation of the novelacylpiperazines of formula I:

A(a) by reacting a 1-acylpiperazine of formula II ##STR4## with a4-substituted 1,1-diarylbutane of formula III ##STR5## wherein R' is asabove defined and Y is halogen, preferably Br or another reactive group,e.g. a mesyl or tosyl ester group, to form a compound of formula I.

A(b) by reacting a 1-(4,4-diaryl-butyl)piperazine of formula IV ##STR6##with an acyl chloride R'-COCl to form a compound of formula I.

The 1-acylpiperazines of formula II employed in the processes accordingto the invention may be prepared by a sequence of operations startingwith:

B(a) a reaction between an acyl chloride R'-COCl and a1-benzyl-piperazine of formula V ##STR7## in chloroform or the like toform a compound of formula VI ##STR8## The compound of formula VI ishydrogenated over a noble metal catalyst to give the compound of formulaII.

In sequence A(a) the compound of formula II is reacted with a compoundof formula III (synthesised according to French Patent M 3695) in asuitable solvent, e.g. a lower alkanol, such as methanol, ethanol,n-butanol and the like, in the presence of an acid acceptor, i.e. anappropriate base, e.g. an alkali metal carbonate or bicarbonate, whichmay be utilised to bind the acid that is liberated during the course ofthe reaction to give the compound of formula I. Elevated temperaturesmay be employed to enhance the rate of reaction.

In sequence A(b) the compound of formula IV (synthesised according toNeth. Appln. No. 6,507,312) is reacted with an acyl chloride R'-COCl ina suitable solvent, e.g. diethyl ether, chloroform, toluene and the liketo form the compounds of formula I. The mixture is reacted over a widerange of temperatures from about 10° C. to about 110° C., although it ispossible to employ temperatures above and below this range.

The writhing test is a frequently used test of analgetic properties(Witkin, L. B. et al., J. Pharmacol. Exp. Ther. 133, 400 (1961)). Ifacetic acid (0.5%, 15 ml/kg) is injected intraperitoneally in mice(NMRI) they will without exception develop a writhing behaviourcharacterized by stretching their hind legs. The drugs to be tested wereadministered subcutaneously to 6 female mice at each dose 20 min. beforethe injection of the acetic acid. After 10 min. The behaviour of themice was studied in 5 min. The ED₅₀ value is the dose blocking thewrithing behaviour in 50% of the animals during the 5 min. study period.

Male mice subjected to prolonged isolation develop aggressive behaviouragainst each other when paired (Yen, C. Y. et al., Arch. Int.Pharmacodyn. 123, 179, (1959); Valzelli, L., Adv. Pharmacol. 5, 79(1967)). All clinically used neuroleptics and antidepressants studied inthis test inhibit this aggressive behaviour although their activity maydiffer. Also anxiolytic drugs, e.g. diazepam, are active on this kind ofaggressive behaviour. The clinical correlation of this test indicatestranquillizing and anxiolytic activities as well as antiaggressiveproperties as such (Duncan, R. L. et al., J. Med. Chem. 13, 1 (1970)).

This type of aggression is interesting because it is known that thiskind of emotional behaviour might be located in limbic structures in thebrain (MacLean, P. D., Psychosom. Med. 11, 338 (1949)).

Every week male NMRI mice, weighing 20-22 g, were isolated in Makroloncages for three weeks with diet and water ad libitum. A piece ofcardboard was placed between the cages to prevent visual contact.

To test aggressiveness the mice were paired in a neutral area, a beaker(14 cm high and diameter 14 cm). A pair is considered aggressive if boththe animals show clear signs of fighting within 5 min. This fighting ischaracterized by biting and vocalization. As soon as fighting is seen,the mice are separated and brought to their home cage. (Every secondmouse is marked.) If only one of two mice exhibit aggressive behaviourthe aggressive one is paired with another to make a well matched,aggressive pair. Animals showing no aggression are discarded. Thefrequency of paired mice exhibiting fighting varies from 5-100 percentdepending on the time of the year. The test substance is administereds.c. (0.2-0.4 ml/20 g). The mice are paired 0.5 h after the injectionfor trials of 5 min. duration.

The ED₅₀ -value (mg/kg) reported is the dose inhibiting aggressivebehaviour among 50 percent of the pairs 0.5 hour after drugadministration.

For the purpose of detecting new psychotropic substances withantiaggressive properties, pharmacologist have used several differentmodels. One model used, the mouse-killing (muricide) by rats (Vogel, J.R. in Industrial Pharmacology, Vol. 2, Antidepressants, Stuart, F. andLal, H., Ed., Futura Publishing Company, 1975, p. 99), is based on anexisting interspecies aggression (Karli, P., Behaviour 10, 81 (1956)).This form of aggressive behaviour which is considered to be of predatorynature, is physiologically and topographically different from otherforms of aggression (O'Boyle, M., Psychol. Bull. 81, 261 (1974)).Mousekilling is a spontaneous behaviour in some rat strains e.g. malehooded Long-Evans rats.

Male hooded Long-Evans rats placed in individual cages were used. Bytesting a number of rats, a colony of rats was obtained that killed amouse whenever introduced into the rats' cage, by biting the mousethrough the cervical spinal cord.

Each rat was tested for mouse-killing behaviour (killing a mouse within5 minutes) prior to each experiment, thus serving as its own positivecontrol. For each dose level 6 positive rats were selected and the testsubstance was administered by subcutaneous injection. Doses wereselected to form a dose-response curve and the mean effective dose(ED₅₀, mg/kg) was calculated by means of linear regression. The ratswere tested at 1, and 2 hours after being injected subcutaneously.##STR9##

                  TABLE 1                                                         ______________________________________                                        Analgetic properties                                                          Compound      R'       ED.sub.50, mg/kg, s.c.                                 ______________________________________                                        1             Et       0.5                                                    2             iso-Pr   1.1                                                    3             cyclo-Pr 0.8                                                    A.sub.1                4.2                                                    Morphine.sup.(a)       1.6                                                    ______________________________________                                         .sup.(a) The Merck Index, 9th Ed., 6108                                  

                  TABLE 2                                                         ______________________________________                                        Spontaneous mouse-killing                                                                       ED.sub.50, mg/kg s.c.                                       Compound     R'         1 hr     2 hr                                         ______________________________________                                        1            Et         1.0      1.8                                          3            cyclo-Pr   2.6      3.7                                          Amitriptyline.sup.(a)   >10      6.4                                          B                       >10      >10                                          ______________________________________                                         .sup.(a) The Merck Index, 9th Ed., 504                                   

                  TABLE 3                                                         ______________________________________                                        Isolation-induced aggressive behaviour.                                       Compound       R'       ED.sub.50, mg/kg, s.c.                                ______________________________________                                        1              Et       2.8                                                   3              cyclo-Pr 1.4                                                   Chlorpromazine.sup.(a)  1.4                                                   Amitriptyline.sup.(b)   5                                                     Diazepam.sup.(c)        6.7                                                   B                       10                                                    ______________________________________                                         .sup.(a) The Merck Index, 9th Ed., 2175                                       .sup.(b) The Merck Index, 9th Ed., 504                                        .sup.(c) The Merck Index, 9th Ed., 2961                                  

The formula I bases are convertible to therapeutically active non-toxicacid addition salts by treatment with an appropriate acid, e.g. aninorganic acid, such as a hydrohalic acid, especially hydrochloric andhydrobromic acid, or sulfuric acid, nitric acid, phosphoric acid and thelike, or an organic acid, such as acetic, propionic, glycolic, lactic,malonic, succinic, fumaric, tartaric, citric and the like acids.Conversely, the salt form can be converted by treatment with alkali intothe free base form.

The compounds I of the invention are very stable in aquous solutions andother kinds of pharmaceutical formulations. Thus, the compounds are wellsuited for preparing sterile solutions.

Effective quantities of any of the foregoing pharmacologically activecompounds of formula I may be administered to a human being or animalfor therapeutic purposes according to usual routes of administration andin usual forms, such as orally in solutions, emulsions, suspensions,pills, tablets and capsules, in pharmaceutically acceptable carriers andparenterally in the form of sterile solutions. For the parenteraladministration of the active substance the carrier or excipient may be asterile, parenterally acceptable liquid, e.g. water, or a parenterallyacceptable oil, e.g. arachidic oil.

Although very small quantities of the active materials of the presentinvention are effective when minor therapy is involved or in the casesof administration to subjects having a relatively low body weight, unitdosages are usually from 2 milligrams upwards preferably 25, 50 or 100milligrams or even higher depending on the condition to be treated andthe age and weight of the patient as well as the response to themedication.

The unit dose may be from 0.1 to 200 milligrams, preferably from 10 to50 milligrams. Daily dosages should preferably range from 10 milligramsto 200 milligrams. The exact individual dosages as well as daily dosageswill, of course, be determined according to standard medical principlesunder the direction of a physician or veterinarian.

The following formulations are representative for all of thepharmacologically active compounds of this invention. Example of asuitable capsule formulation:

    ______________________________________                                                        per capsule, mg                                               ______________________________________                                        Active ingredient, as salt                                                                       10                                                         Lactose           250                                                         Starch            120                                                         Magnesium stearate                                                                               5                                                          Total             385                                                         ______________________________________                                    

In case of higher amounts of active ingredient, the amount of lactoseused may be reduced.

Example of a suitable tablet formulation:

    ______________________________________                                                          per tablet, mg                                              ______________________________________                                        Active ingredient, as salt                                                                        10                                                        Potato starch       90                                                        Colloidal silica    10                                                        Talc                20                                                        Magnesium stearate   2                                                        5% Aqueous solution of gelatin                                                                    25                                                        Total               157                                                       ______________________________________                                    

The pharmaceutical preparations may also contain therapeutically usefulsubstances other than the pharmacologically active compounds of formulaI.

The following examples are intended to illustrate the present invention,without limiting the scope thereof.

EXAMPLE 1 1-Cyclohexanecarbonyl-4-benzylpiperazine

To a solution of 21.2 g (0.12 mole) of 1-benzylpiperazine in 100 ml ofCHCl₃ was added dropwise over a period of 30 minutes a solution of 15.0g (0.10 mole) of cyclohexanecarbonyl chloride in 50 ml of CHCl₃. Themixture was allowed to stand at room temperature during 45 minutes andwas made basic with 5 g of sodium hydroxide in 50 ml of water. Thenonaqueous layer was separated, dried over sodium sulphate andconcentrated. The residue was distilled b.p. 150°-56° C. at 0.1-0.2 mmHgto give 21.2 g of 1-cyclohexanecarbonyl-4-benzylpiperazine.

EXAMPLE 2 1-Cyclohexanecarbonylpiperazine hydrochloride

14.3 g (0.05 mole) of 1-cyclohexanecarbonyl-4-benzylpiperazine dissolvedin 250 ml of ethanol and acidified with conc. HCl was treated withhydrogen over a palladium catalyst at 1500 psi and 100° C. The catalystwas removed by filtration and the solvent removed under reducedpressure. The residue was dissolved in isopropanol. On short standing awhite crystalline precipitate appeared which was collected by filtrationto give 10.0 g of 1-cyclohexanecarbonylpiperazine hydrochloride.

EXAMPLE 31-Cyclohexanecarbonyl-4-[4,4-(di-p-fluorophenyl)butyl]piperazinehydrochloride

To 7.0 g (0.03 mole) of 1-cyclohexanecarbonylpiperazine hydrochloridewas added a solution of 1.5 g of sodium hydroxide in 50 ml of water. Themixture was extracted with CHCl₃. The combined extracts were dried oversodium sulphate and concentrated. The residue was dissolved in 10 ml ofethanol. 10.0 g (0.036 mole) of 4-chloro-1,1-(di-fluorophenyl)-butaneand 5.0 g of sodium bicarbonate was added. The mixture was heated atreflux for 36 hours. 100 ml of water was added. The mixture wasextracted twice with CHCl₃. The combined extracts were dried over sodiumsulphate and concentrated. The residue was dissolved in ethanol-etherand the hydrochloride was precipitated with ethanolic HCl. The solid wascollected by filtration and recrystallised from 2-butanone to give 8.2 gof 1-cyclohexanecarbonyl-4-[4,4-(di-p-fluorophenyl)butyl]piperazinehydrochloride. Melting point 156°-58° C.

EXAMPLE 4 1-Ethylcarbonyl-4-[4,4-(di-p-fluorophenyl)butyl]-piperazinehydrochloride

To a solution of 3.3 g (0.01 mole) of1-[4,4-(di-p-fluorophenyl)butyl]piperazine in 15 ml of CHCl₃ was addeddropwise over a period of 15 minutes 1.05 g (0.011 mole) of propionylchloride in 15 ml of CHCl₃. The mixture was allowed to stand at roomtemperature during 1 hour and was made basic with 0.8 g of sodiumhydroxide in 25 ml of water. The nonaqueous layer was separated, driedover sodium sulphate and concentrated.

The residual oil was dissolved in 2-butanone and the hydrochloride wasprecipitated with ethanolic HCl. The solid was collected by filtrationand recrystallized from 2-butanone to give 3.2 g of1-ethylcarbonyl-4-[4,4-(di-p-fluorophenyl)butyl]-piperazinehydrochloride. Melting point 171°-173° C.

                  TABLE IV                                                        ______________________________________                                         ##STR10##                                                                           Method in                                                                     accordance               M.p..sup.(a)                                  Example                                                                              with example                                                                              R'           °C.                                                                            Salt                                  ______________________________________                                        5      4           n-C.sub.3 H.sub.7                                                                          123-124 HCl                                   6      4           iso-C.sub.3 H.sub.7                                                                        156-158 HCl                                   7      4           cyclo-C.sub.3 H.sub.5                                                                      165-166 HCl                                   8      4           n-C.sub.4 H.sub.9                                                                          143-144 HCl                                   9      1 + 2 + 3   tert-C.sub.4 H.sub.9                                                                       174-175 HCl                                   10     4           n-C.sub.7 H.sub.15                                                                         120-121 HCl                                   11     4                                                                                          ##STR11##   191-192 HCl                                   12     4                                                                                          ##STR12##   221-222 HCl                                   13     4                                                                                          ##STR13##   186-187 HCl                                   14     4                                                                                          ##STR14##   173-174 HCl                                   ______________________________________                                         .sup.(a) Melting points are uncorrected                                  

What we claim is:
 1. A compound having the formula: ##STR15## wherein R'is selected from the group consisting of alkyl straight or branchchained having from 2 to 10 carbon atoms, cycloalkyl having from 3 to 8carbon atoms, aralkyl having from 7 to 9 carbon atoms, phenyl andsubstituted phenyl wherein the substituents of the substituted phenylare selected from the group consisting of one to three F, Cl, Br, loweralkyl having from 1 to 5 carbon atoms, lower alkoxy having from 1 to 5carbon atoms, alkylenedioxy having from 1 to 3 carbon atoms, --CF₃ and--CN and pharmaceutically acceptable salts thereof.
 2. A compound of theformula ##STR16## wherein R' is ethyl.
 3. A compound of the formula##STR17## wherein R' is isopropyl.
 4. A compound of the formula##STR18## wherein R' is cyclopropyl.
 5. A compound of the formula##STR19## wherein R' is propyl.
 6. A pharmaceutical compositioncharacterized in that it contains a therapeutically effective amount ofa compound of formula I as defined in claim 1 in combination with aconventional pharmaceutically acceptable carrier.
 7. A method oftreating mammals for anti-aggressive purposes comprising administratingan anti-aggressive effective amount of a compound of Formula I asdefined in claim
 1. 8. A method of treating mammals suffering frommental disorders comprising administrating a therapeutically effectiveamount of a compound of Formula I as defined in claim
 1. 9. A method oftreating mammals for analgetic purposes comprising administrating ananalgetically effective amount of a compound of Formula I as defined inclaim 1.